USP2 inhibition unleashes CD47-restrained phagocytosis and enhances anti-tumor immunity
Abstract The CD47/SIRPα axis conveys a ‘don’t eat me’ signal, thereby thwarting the phagocytic clearance of tumor cells. Although blocking antibodies targeting CD47 have demonstrated promising anti-tumor effects in preclinical models, clinical trials involving human cancer patients have not yielded...
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| Format: | Article |
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59621-5 |
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| author | Panpan Dai Yishuang Sun Zhengrong Huang Yu-Tong Liu Minling Gao Hai-Ming Liu Jie Shi Chuan He Bolin Xiang Yingmeng Yao Haisheng Yu Gaoshan Xu Lijun Kong Xiangling Xiao Xiyong Wang Xue Zhang Wenjun Xiong Jing Hu Dandan Lin Bo Zhong Gang Chen Yan Gong Conghua Xie Jinfang Zhang |
| author_facet | Panpan Dai Yishuang Sun Zhengrong Huang Yu-Tong Liu Minling Gao Hai-Ming Liu Jie Shi Chuan He Bolin Xiang Yingmeng Yao Haisheng Yu Gaoshan Xu Lijun Kong Xiangling Xiao Xiyong Wang Xue Zhang Wenjun Xiong Jing Hu Dandan Lin Bo Zhong Gang Chen Yan Gong Conghua Xie Jinfang Zhang |
| author_sort | Panpan Dai |
| collection | DOAJ |
| description | Abstract The CD47/SIRPα axis conveys a ‘don’t eat me’ signal, thereby thwarting the phagocytic clearance of tumor cells. Although blocking antibodies targeting CD47 have demonstrated promising anti-tumor effects in preclinical models, clinical trials involving human cancer patients have not yielded ideal results. Exploring the regulatory mechanisms of CD47 is imperative for devising more efficacious combinational therapies. Here, we report that inhibiting USP2 prompts CD47 degradation and reshapes the tumor microenvironment (TME), thereby enhancing anti-PD-1 immunotherapy. Mechanistically, USP2 interacts with CD47, stabilizing it through deubiquitination. USP2 inhibition destabilizes CD47, thereby boosting macrophage phagocytosis. Single-cell RNA sequencing shows USP2 inhibition reprograms TME, evidenced by increasing M1 macrophages and CD8+ T cells while reducing M2 macrophages. Combining ML364 with anti-PD-1 reduces tumor burden in mouse models. Clinically, low USP2 expression predicts a better response to anti-PD-1 treatment. Our findings uncover the regulatory mechanism of CD47 by USP2 and targeting this axis boosts anti-tumor immunity. |
| format | Article |
| id | doaj-art-befef078cf094cd4aac6daa1144031d4 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-befef078cf094cd4aac6daa1144031d42025-08-20T03:53:57ZengNature PortfolioNature Communications2041-17232025-05-0116112210.1038/s41467-025-59621-5USP2 inhibition unleashes CD47-restrained phagocytosis and enhances anti-tumor immunityPanpan Dai0Yishuang Sun1Zhengrong Huang2Yu-Tong Liu3Minling Gao4Hai-Ming Liu5Jie Shi6Chuan He7Bolin Xiang8Yingmeng Yao9Haisheng Yu10Gaoshan Xu11Lijun Kong12Xiangling Xiao13Xiyong Wang14Xue Zhang15Wenjun Xiong16Jing Hu17Dandan Lin18Bo Zhong19Gang Chen20Yan Gong21Conghua Xie22Jinfang Zhang23Department of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan UniversityDepartment of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan UniversityTumor Precision Diagnosis and Treatment Technology and Translational Medicine, Hubei Engineering Research Center, Zhongnan Hospital of Wuhan UniversityState Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan UniversityDepartment of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan UniversityState Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan UniversityDepartment of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan UniversityDepartment of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan UniversityDepartment of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan UniversityDepartment of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan UniversityDepartment of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan UniversityDepartment of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan UniversityDepartment of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan UniversityDepartment of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan UniversityDepartment of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan UniversityDepartment of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan UniversityDepartment of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan UniversityDepartment of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan UniversityCancer Center, Renmin Hospital of Wuhan UniversityState Key Laboratory of Metabolism and Regulation in Complex Organisms, College of Life Sciences, Taikang Center for Life and Medical Sciences, Wuhan UniversityState Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan UniversityTumor Precision Diagnosis and Treatment Technology and Translational Medicine, Hubei Engineering Research Center, Zhongnan Hospital of Wuhan UniversityDepartment of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan UniversityDepartment of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan UniversityAbstract The CD47/SIRPα axis conveys a ‘don’t eat me’ signal, thereby thwarting the phagocytic clearance of tumor cells. Although blocking antibodies targeting CD47 have demonstrated promising anti-tumor effects in preclinical models, clinical trials involving human cancer patients have not yielded ideal results. Exploring the regulatory mechanisms of CD47 is imperative for devising more efficacious combinational therapies. Here, we report that inhibiting USP2 prompts CD47 degradation and reshapes the tumor microenvironment (TME), thereby enhancing anti-PD-1 immunotherapy. Mechanistically, USP2 interacts with CD47, stabilizing it through deubiquitination. USP2 inhibition destabilizes CD47, thereby boosting macrophage phagocytosis. Single-cell RNA sequencing shows USP2 inhibition reprograms TME, evidenced by increasing M1 macrophages and CD8+ T cells while reducing M2 macrophages. Combining ML364 with anti-PD-1 reduces tumor burden in mouse models. Clinically, low USP2 expression predicts a better response to anti-PD-1 treatment. Our findings uncover the regulatory mechanism of CD47 by USP2 and targeting this axis boosts anti-tumor immunity.https://doi.org/10.1038/s41467-025-59621-5 |
| spellingShingle | Panpan Dai Yishuang Sun Zhengrong Huang Yu-Tong Liu Minling Gao Hai-Ming Liu Jie Shi Chuan He Bolin Xiang Yingmeng Yao Haisheng Yu Gaoshan Xu Lijun Kong Xiangling Xiao Xiyong Wang Xue Zhang Wenjun Xiong Jing Hu Dandan Lin Bo Zhong Gang Chen Yan Gong Conghua Xie Jinfang Zhang USP2 inhibition unleashes CD47-restrained phagocytosis and enhances anti-tumor immunity Nature Communications |
| title | USP2 inhibition unleashes CD47-restrained phagocytosis and enhances anti-tumor immunity |
| title_full | USP2 inhibition unleashes CD47-restrained phagocytosis and enhances anti-tumor immunity |
| title_fullStr | USP2 inhibition unleashes CD47-restrained phagocytosis and enhances anti-tumor immunity |
| title_full_unstemmed | USP2 inhibition unleashes CD47-restrained phagocytosis and enhances anti-tumor immunity |
| title_short | USP2 inhibition unleashes CD47-restrained phagocytosis and enhances anti-tumor immunity |
| title_sort | usp2 inhibition unleashes cd47 restrained phagocytosis and enhances anti tumor immunity |
| url | https://doi.org/10.1038/s41467-025-59621-5 |
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